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The ethyl acetate-extractable metabolites of phenanthridine as formed in vitro with Aroclor-induced rat liver homogenate were isolated and structurally identified. The relative amounts of these metabolites were determined using [6-14C]phenanthridine. The major metabolites of phenanthridine formed under these incubation conditions were identified as phenanthridine-N-oxide, 1,2-dihydroxy-1,2-dihydrophenanthridine, and 9,10-dihydroxy-9,10-dihydrophenanthridine. Phenanthridone and 2-hydroxyphenanthridine were identified as minor metabolites. These data were obtained using an identical incubation mixture as employed in mutagenicity assays. It is suggested that metabolites in addition to phenanthridone are likely to contribute to mutagenicity of phenanthridine observed in assays performed with metabolic activation.
The comparative metabolism of phenanthridine (3,4-benzoquinoline) by rat lung and liver microsomes has been investigated. The array of metabolites produced by induced lung and liver are qualitatively similar. Phenanthridone has been identified as a phenanthridine metabolite produced by induced rat liver and lung. Phenanthridone is directly mutagenic in Salmonella tester strain TA-98 while phenanthridine is not. Although phenanthridone is more mutagenic than phenanthridine after incubation with rat liver 9000g supernatant fraction, it is less cytotoxic to Chinese hamster ovary cells in vitro.
The nitroimidazole-linked phenanthridine series of compounds (NLP-1, 2, and 3) were synthesized under the assumption that it should be possible to enhance the molar efficiency of 2-nitroimidazoles as hypoxic cell radiosensitizers and cytotoxins by targeting them to their likely site of action, DNA. The targeting group chosen was the phenanthridine moiety, the major component of the classical DNA intercalating compound, ethidium bromide. The sole difference between the compounds is the length of the hydrocarbon chain linking the nitroimidazole to the phenanthridine. The phenanthridine group with a three-carbon side chain, P-1, was also synthesized to allow studies on the effect of the targeting group by itself. The ability of the compounds to bind to DNA is inversely proportional to their linker chain length with binding constant values ranging from approximately 1 x 10(5) mol-1 for NLP-2 to 6 x 10(5) mol-1 for NLP-3. The NLP compounds show selective toxicity to hypoxic cells at 37 degrees C at external drug concentrations 10-40 times lower than would be required for untargeted 2-nitroimidazoles such as misonidazole in vitro. Toxicity to both hypoxic and aerobic cells is dependent on the linker chain: the shorter the chain, the greater the toxicity. In addition, the NLP compounds radiosensitize hypoxic cells at external drug concentrations as low as 0.05 mM with almost the full oxygen effect being observed at a concentration of 0.5 mM. These concentrations are 10-100 times lower than would be required for similar radiosensitization using misonidazole. Radiosensitizing ability is independent of linker chain length. The present compounds represent prototypes for further studies of the efficacy and mechanism of action of 2-nitroimidazoles targeted to DNA by linkage to an intercalating group.
From cell cultures of Eschscholtzia californica and their spent medium, three new benzo[c]phenanthridine alkaloids--namely 10-hydroxysanguinarine [2a], 12-hydroxychelirubine [4a], and 10-hydroxychelerythrine [7a]--and two new dihydrobenzo[c]phenanthridine alkaloids--10-hydroxydihydrosanguinarine [2b] and 12-hydroxydihydrochelirubine [4b]--together with the known constituents sanguinarine [1a], chelirubine [3a], macarpine [5a], dihydrosanguinarine [1b], dihydrochelirubine [3b], and dihydromacarpine [5b], were isolated and characterized. Structure elucidations were done by 1H nmr, decoupling experiments, and NOESY spectra. Isolated microsomes from E. californica, the site of hydroxylation activity within the cells, contained the whole set 1b to 8b of 5,6-dihydrobenzo[c]phenanthridines. A scheme for the biosynthesis of macarpine [5a] from protopine [9] via dihydrosanguinarine [1b] is presented.
trans-10,11-Dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[a]phenan thridine (4a, dihydrexidine) has been found to be a highly potent and selective agonist of the dopamine D1 receptor in rat brain. Dihydrexidine had an EC50 of approximately 70 nM in activating dopamine-sensitive rat striatal adenylate cyclase and a maximal stimulation equal to or slightly greater than that produced by dopamine. Dihydrexidine had an IC50 of 12 nM in competing for [3H]SCH23390 (1a) binding sites in rat striatal homogenate, and of 120 nM versus [3H]spiperone. These data demonstrate that dihydroxidine has about ten-fold selectivity for D1/D2 receptors. More importantly, however, is the fact that dihydrexidine is a full agonist. Previously available agents, such as SKF38393 (1b), while being somewhat more selective for the D1 receptor, are only partial agonists. The isomeric cis-dihydroxybenzo[a]-phenanthridine neither stimulated cAMP synthesis nor inhibited the cAMP synthesis induced by dopamine. The cis isomer also lacked appreciable affinity for [3H]-1a binding sites. N-Methylation of the title compound decreased affinity for D1 sites about 7-8-fold and markedly decreased ability to stimulate adenylate cyclase. Addition of an N-n-propyl group reduced affinity for D1 sites by about 50-fold and essentially abolished the ability to stimulate adenylate cyclase. However, this latter derivative had twice the affinity of the D2-selective agonist quinpirole for the D2 receptor. The results are discussed in the context of a conceptual model for the agonist state of the D1 receptor.
Of five newly synthesized benzo[c]phenanthridine derivatives tested, the two compounds, BPD-I and BPD-II were found to have potent anti-edematous activity with intraperitoneal administration to S.D. rats. BPD-I showed a marked inhibitory effect against acute inflammation such as induced rat paw edema and leucocyte emigration and protein exudation by means of CMC pouch method and capillary permeability enhancement induced by various phlogists. This compound also inhibited subacute and chronic inflammatory responses such as granuloma formation induced by croton oil or cotton pellet. The anti-inflammatory activities of this compound resembled those of hydrocortisone. The inhibitory effects of carragenan edema and capillary permeability enhancement by ATP were strikingly reduced in adrenalectomized rats suggesting involvement of the hypophysis-adrenal systems. Rat serum corticosterone level and hepatic tyrosine aminotransferase activity (TAT) were then measured after BPD-I injection. The serum corticosterone level was increased and shortly after the elevation of corticosterone, hepatic TAT levels also increased. Thus it is concluded that the corticosterone release from adrenal gland plays a role in the anti-inflammatory action of BPD-I.
The conditions of the electrochemical reduction and oxidation as well as those of thermal demethylation of quaternary benzo(c)-phenanthridine alkaloids namely chelerythrine (1), sanguinarine (2), and fagaronine (3) were studied. Differences in their electrochemical and thermal behavior are correlated with the results obtained from biotransformation studies with liver microsomal fraction.
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We have synthesised an homologous series of n-bromoalkylphenanthridinium bromides and studied their DNA-binding and antitumour properties. Each of these compounds has the capacity both to intercalate and alkylate DNA. Dialysis measurements reveal a relatively high affinity for calf thymus DNA, being about 10(5) M-1 at ionic strength 0.01. Incubating calf thymus DNA-ligand complexes having a ligand-to-basepair ratio of 0.4 at 37 degrees C for 18 h leads to maximum alkylation levels of about one ligand molecule bound irreversibly per 40 basepairs. The reactivity of these compounds towards DNA is chain-length dependent, the n-decyl compound, for example, requiring about 10-times the ligand-to-basepair input ratio of the n-hexyl derivative to reach the same level of alkylation. The limited degree of alkylation is a consequence of conversion of the alkylbromides to the less reactive alkylchlorides in the buffer medium. The results of DNA sequencing experiments indicate that the n-hexyl derivative alkylates at guanines occurring in 5'-GT-3' sequences and in runs of guanines [(Gp)n]. The corresponding n-decyl compound, on the other hand, is highly selective for guanines in 5'-GT-3' sequences only and also reacts weakly with some adenines. None of the phenanthridinium compounds showed significant antitumour activity in the P388 murine leukaemia test system.
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In contrast to the many selective dopamine (DA) D2 receptor agonists known, only two prototypes of selective D1 receptor agonists have been described; both show preference for the periphery due to their catechol partial structures. Our search for non-catechol, selective D1 agonists was based on the hypothesis that D1 selectivity could be conferred upon ergolines by annulation with a phenyl ring. The target molecules, trans-4,6,6a,7,8,12b-hexahydroindolo-[4,3-ab]phenanthridi nes ("benzergolines"), were efficiently synthesized by using the Ninomiya enamide photocyclization reaction. These compounds were found to be as active as the most potent D1 agonists in the adenylate cyclase D1 receptor model, but showed no activity in the ACh release D2 receptor assay. The acquired subtype selectivity of the novel structures was accompanied by an enhanced potency and efficacy as compared to the corresponding ergolines. This points to a D1 affinity enhancing, D2 receptor discriminating role for the additional phenyl group and provides further support for the existence of a D1 receptor specific accessory aryl binding site. Thus the benzergolines represent the first structural class of potent and selective D1 agonists lacking a catechol group which should allow an efficient central nervous system penetration. On the basis of these results, the D1 agonist pharmacophore has to be revised in the sense that potent activity requires neither a catechol function nor an orthogonal conformation of the aromatic rings.
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